Up to 70% of the general population has one or more gastrointestinal complaints annually, and while incurring extremely high costs for treatment, the pathophysiology of these symptoms remains largely unexplained. In the last decade, an increasing number of studies have demonstrated an association between gastrointestinal symptoms and diseases related to altered metabolic functions (such as insulin resistance or metabolic syndrome). Furthermore, changes in body fat observed in obesity, or changes in body mass index (as observed in patients suffering from functional gastrointestinal disorders) have been associated with gastrointestinal symptoms. While the mechanisms underlying these associations are unknown, accumulating evidence clearly demonstrates chronic psychological stress as a key risk factor in this cluster of diseases. Yet, the link(s) between chronic stress, altered metabolic pathways and gastrointestinal dysfunctions has not been investigated. In view of the lack of accuracy of life events reporting and dating in non experimental clinical settings, it is critical to develop preclinical approaches to address the mechanisms underlying the effect of stress in these conditions. In our group, we recently showed that neuropeptides such as substance P, corticotropin-releasing hormone, and neurotensin, that are involved in both the stress response and the modulation of gastrointestinal motility, can stimulate proliferation in human preadipocytes, suggesting their participation in fat expansion, a prominent feature of several disease states, including type II diabetes. In addition, we have demonstrated the ability of these neuropeptides not only to induce pro-inflammatory signaling in adipocytes, but also to affect their response to insulin. Our general hypothesis is that stress- induced changes in neuropeptides levels within visceral adipose tissue trigger adipocyte specific impairment of insulin signaling, which contributes to changes in gastrointestinal motility. Using 2 rat models of chronic psychological stress validated for irritable bowel syndrome and depression, we propose to evaluate 1) whether chronic stress affects visceral adiposity and the expression of neuropeptides and examine their effect on adipocytes-associated insulin signaling and 2) the role of chronic psychological stress in the development of glucose intolerance and insulin resistance and determine whether these responses are involved in the modulation of gastrointestinal motility. We anticipate that the work proposed in this application will significantly increase our knowledge on the role of adipose tissue in alterations of gastrointestinal functions associated with a cluster of stress-related diseases and provide new targets for future therapeutic approaches for the treatment of several common stress-associated gastrointestinal diseases. This proposal will establish a new Collaborative Research Program by bringing together complementary fields and expertise of stress-related gastrointestinal physiology and pathophysiology and motility, adipocyte biology and metabolism, neuropeptide signaling and intestinal inflammation based at the Division of Digestive Diseases at UCLA and the GI unit at the Los Angeles Veterans Administration Hospital. The proposed funding will support 6 researchers (including new hires) and the acquisition of a new instrument (EchoMRI) that will be applicable not only to this project, but to ongoing collaborative research in the UCLA campus linking changes in adiposity with the pathophysiology of several disease states. Moreover, the requested funds are specifically aimed at accelerating the acquisition of proof-of-concept data suitable for establishing future collaborative R01 or P01 NIH proposals, NIH-Private Partnership Opportunities and/or clinical trials that will rapidly generate additional employment opportunities. PUBLIC HEALTH RELEVANCE: A strong association between a cluster of diseases, including metabolic syndrome, type II diabetes, obesity, and the development of gastrointestinal symptoms has been consistently described in clinical settings. While chronic psychological stress has been described as a key risk factor in these conditions, the link between chronic stress, adipocyte responses associated with altered metabolic pathways, and gastrointestinal dysfunctions has not been investigated. Our study, using animal models of chronic psychological stress, proposes to fill this gap.